Design, Synthesis, Biological Evaluation, and In Silico Analysis of Novel Antifungal Agents Targeting <i>Trichophyton</i> Species

Terbinafine (Tb) is the primary commercial treatment for superficial nail infections; however, resistance is an emerging public health concern, largely driven by point mutations in the squalene epoxidase (SQLE) gene that reduce the drug's effectiveness. In this work, five novel synthetic compounds were developed and evaluated for their antifungal activity against 24 clinical isolates of Trichophyton rubrum and Trichophyton mentagrophytes. Among them, compound antifungal 2 demonstrated potent activity at the nanomolar level (ca. 73 nM), surpassing the efficacy of Tb (ca. 253 nM), and with less risk of resistance due to its rational molecular design. Molecular docking and molecular dynamics studies, conducted using a model of fungal SQLE (SE), supported the efficacy of compound 2 as a potential antifungal agent and provided reliable structure-activity relationship insights. Our results highlight the potential of combining propiolaldehyde and sulfonamide-based scaffolds to offer a promising foundation for the rational design of next-generation antifungal agents.